DESCRIPTION (Applicant's abstract): Gastrointestinal (GI) disturbances are not normally life-threatening but do profoundly affect quality of life. Diabetic patients often experience a wide range of GI discomforts including heartburn, nausea, vomiting, diarrhea, constipation, fecal incontinence and abdominal pain. Many patients have abnormalities in motility arising from identifiable conditions; but over 50% of GI complaints are idiopathic and are indicative of autonomic neuropathy. Both enteric nerves in and sympathetic nerves to the GI tract undergo neuropathy in animal models of diabetes as supported by immunohistochemical, histological, and functional data. A streptozotocin-induced diabetic guinea pig model will be used to isolate and evaluate alterations in sympathetic and enteric nerve activity at the histochemical, functional and cellular level. Neuropathy of enteric neurons will be investigated immunohistochemically by quantifying enzyme and peptide content of the small intestine, functionally by recording contractions/ relaxations from circular/ longitudinal smooth muscle strips of small intestine and cellularly by recording junction potentials from smooth muscle cells. Neuropathy of sympathetic neurons will be evaluated histochemically by quantifying norepinephrine (NE) content of small intestine and cellularly by recording NE mediated inhibitory postsynaptic potentials from submucosal neurons and by evaluating presynaptic inhibition of enteric neurotransmission by NE. Experimental data will be correlated with metabolic indices (body weight, glycosylated hemoglobin and plasma glucose) to determine normal control deviations and degree of diabetic severity with the intent of identifying a threshold for GI dysfunction. By defining the individual contribution of sympathetic and enteric neuropathies to dysfunctional GI motility, targets for therapeutic intervention to improve patient quality of life will be pinpointed. Adaptations of enteric neurons to diabetes will provide insight into enteric plasticity occurring in other GI diseases such as neuronal intestinal dysplasia, achalasia, scleroderma, pyloric stenosis, idiopathic constipation, diverticular disease, Parkinson's disease, and paraneoplastic syndromes.